Inhibitory effects of epigallocatechin‐3 gallate, a polyphenol in green tea, on tumor‐associated endothelial cells and endothelial progenitor cells

Abstract

The polyphenol epigallocatechin-3 gallate (EGCG) in green tea suppresses tumor growth by direct action on tumor cells and by inhibition of angiogenesis, but it is not known whether it specifically inhibits tumor angiogenesis. We examined the antiangiogenic effect of EGCG on tumor-associated endothelial cells (TEC), endothelial progenitor cells (EPC), and normal endothelial cells (NEC). EGCG suppressed the migration of TEC and EPC but not NEC. EGCG also inhibited the phosphorylation of Akt in TEC but not in NEC. Furthermore, vascular endothelial growth factor-induced mobilization of EPC into circulation was inhibited by EGCG. MMP-9 in the bone marrow plasma plays key roles in EPC mobilization into circulation. We observed that expression of MMP-9 mRNA was downregulated by EGCG in mouse bone marrow stromal cells. In an in vivo model, EGCG suppressed growth of melanoma and reduced microvessel density. Our study showed that EGCG has selective antiangiogenic effects on TEC and EPC. It is suggested that EGCG could be a promising angiogenesis inhibitor for cancer therapy. T ea is one of the most popular beverages consumed worldwide. Drinking tea, especially green tea, inhibits the growth of several tumors in animal models, including cancers of the skin, lung, esophagus, breast, stomach, small intestine, colon, liver, pancreas, and mammary glands, (1,2) and is associated with a lower incidence of cancer in humans.(1,3,4) The components of green tea responsible for these effects are catechins, which are polyphenols with potent antioxidant capacity that have been shown to inhibit mutation, tumor cell growth, tumor initiation, tumor progression, and the activity of urokinase and MMP, which are crucial for cancer growth.(5-7) Among these catechins, epigallocatechin-3 gallate (EGCG) has the highest antioxidant capacity and is an effective inhibitor of corneal vascularization in vivo. (8) The tumor microenvironment has recently been regarded as a target of cancer chemoprevention because it plays an important role in tumorigenesis and tumor progression.(9) Tumor angiogenesis is one of the key processes within the tumor microenvironment, and controlling this process is a very important strategy for preventing invasive cancers.(10) Many molecules regulating tumor angiogenesis have been identified and characterized recently, including vascular endothelial growth factor (VEGF). (11,12) EGCG has also been shown to inhibit cell proliferation, (13) binding of VEGF to its receptors, (14) phosphorylation of VEGF receptor (VEGFR) 2, (15) MMP activity, (13) and interleukin-8 production (16) in normal endothelial cells such as human umbilical vein endothelial cells.An important concept in tumor angiogenesis is that tumor blood vessels contain endothelial cells that are genetically normal and stable, whereas tumor cells are typically genetically unstable.(17) However, tumor vessels and tumor-associated endothelial cells (TEC) differ from their normal counterparts in many respects. (18)(19)(20) Tumor vessels show structural changes such as ...

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

“…54 Akt is also considered an important regulator of several signaling pathways that can lead to autoimmunity. 55 There have been mixed reports regarding the effects of EGCG on Akt depending on the cell type studied, as EGCG is shown to reduce Akt phosphorylation in endothelial cells, tumor associated endothelial cells and caco-2 cells, [56][57][58][59] but activate Akt in lung carcinoma cells and osteoblasts. 60,61 Here, we show that EGCG reduces Akt activation and subsequently inflammation in immune stimulated mesangial cells.…”

Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy

“…TECs from OS-RC-2 tumor tissue were successfully collected, as described previously [17][18][19][20][21][22]. As shown in Fig.…”

“…TECs were isolated, as described previously [17][18][19][20][21][22]. In a typical procedure, the TECs were isolated from OS-RC-2 tumors and dermal tissue in tumor-bearing mice using a magnetic cell sorting system (MACS; Milteny Biotec, Tokyo, Japan).…”

RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system

“…These media were supplemented with 10% fetal bovine serum, penicillin (100 U/mL) and streptomycin (100 μg/mL). TECs, which were previously isolated by Ohga et al [31], and HUVEC were cultured in EBM-2 medium supplemented with 2% FBS (v/v) and bullet kits (Lonza, Walkersville, MD). All cells were maintained at 37°C in a 5% CO 2 humidified atmosphere.…”